Within the last few years, our laboratory discovered that important structural motifs in medicinal alkaloids, indoles and piperidines, could be synthesized with extraordinary ease using highly unusual reactivity. The activation of an unstrained carbon-carbon sigma bond (C-C bond), long thought to be 'inert' except under high temperature and/or pressure, can quickly build the synthetically challenging all-carbon quaternary center of these frameworks in mild conditions from simple materials. The objective of this application is to discover C-CN activation conditions that are broadly applicable to the synthesis of biologically active alkaloids. Many questions remain before C-CN activation can widely used. Little is known about the reaction from a mechanistic standpoint, how aryl- or quaternary carbon-substituted alkenes might undergo migratory insertion in a synthetically useful manner, or whether other similar organonitriles will undergo C-CN activation. We will test our central hypothesis that C-CN activation will be tolerant of other functionalities while providing densely functionalized alkaloid cores from simple building blocks. In Aim 1, we describe how we will construct a mechanistic model that will allow rational optimization as we tackle challenging C-CN activation reactions. In Aim 2, we describe how the synthesis of several rare, biologically active alkaloids will allow us to advance cyanoamidation methodology while providing the synthetic community with examples how C-CN activation might be used, and provide materials to probe biomedical questions. In Aim 3, we detail how additional biologically active frameworks outside the two main motifs might be constructed by the controlled activation of cyanoformate esters. We also propose that dual cyanoamidation and sequential cyanoamidation/cyanoesterification of easily prepared 1,3-dienes will be exceptionally powerful approach to the asymmetric synthesis of molecules containing vicinal all-carbon quaternary stereocenters. Completion of our objectives will provide four classes of naturally scarce, structurally challenging, biological active materials for further therapeutic discovery, but will also deepen our understanding of cyanoamidation. A mechanistic model will not only incorporate innovative experiments that probe potentially relevant equilibria and trap putative intermediates, but will also guide our thinking in developing new chemistry. Our studies on cyanoesterification and tandem C-CN activation will expand the repertoire of targets accessible by C-CN activation. In addition to C-CN activation, several additional underdeveloped methods in synthesis are proposed during the syntheses of our targeted alkaloids. We hope, however, that the better understanding of C-C activation and demonstrated use in the synthesis of complex alkaloids will provide the synthetic community with a highly efficient and reliable method for the preparation of alkaloids.